The goal of this proposal is to develop a clinical trials network capable of engaging in several clinical trials of the treatments of uveitis and its complications. The MUST Research Group (RG) structure already is in place, and processes have been developed for review, approval, and prioritization of clinical trials. Four clinical research studies are proposed as the initial activities of the proposed network, which represent the specific aims of the proposal. These are: 1) To continue the current MUST Trial follow-up past the original two-year determination of the primary outcome for an additional 6 years. This long-term follow-up will enable the MUST RG to evaluate the long-term consequences of the two treatment paradigms: regional corticosteroid treatment v. systemic therapy with corticosteroids and immunosuppression; 2) To compare the relative effectiveness of adalimumab (Humira(R), Abbott Laboratories, Abbott Park, IL), a fully human monoclonal antibody to TNF-a v. conventional immunosuppression for patients with severe uveitis requiring immunosuppressive drug therapy. Adalimumab already is approved by the US Food and Drug Administration (FDA) for the treatment of several autoimmune or autoinflammatory diseases, such as rheumatoid arthritis, and preliminary data suggest that it is effective as a corticosteroid-sparing agent in patients with uveitis; 3) To compare periocular v. intravitreal corticosteroids for the treatment of macular edema in patients with uveitis. Both periocular and intravitreal corticosteroids appear to be effective for the treatment of macular edema in patients with uveitis, but no comparative trials have been performed. Many clinicians believe that intravitreal corticosteroids are more effective than periocular corticosteroids for this indication, but that they also have higher rates of side effects; and 4) To compare intravitreal ranibizumab (Lucentis(R), Genentech Inc., San Francisco, CA), a monoclonal antibody to vascular endothelial growth factor, to intravitreal corticosteroids for the treatment of refractory macular edema in patients with uveitis. A pilot study suggested that ranibizumab was effective in the treatment of uveitic macular edema and that potentially it may have less ocular side effects than corticosteroids. However, the relative efficacy of the two treatments is unknown. RELEVANCE: Non-infectious uveitis is associated with high rates of visual loss and usually requires long-term therapy, often with oral corticosteroids, supplemented, when indicated, by immunosuppressive (corticosteroid- sparing) drugs. Visual loss often is caused by structural complications, e.g., macular edema. We propose to carry out a series of clinical studies to provide an evidence base for the management of these conditions.